I. Field of the Invention
The present invention is related generally to transdermal delivery of active compounds by iontophoresis. Specifically, this invention relates to a method and system for the transdermal delivery of corticosteroid drug compounds, particularly in water-soluble sodium salt forms including dexamethasone sodium phosphate and betamethasone sodium phosphate. Further, this invention provides a wearable iontophoresis system, which can be used to provide both rapid pain relief and sustained action for the prevention of pain recurrence.
II. Related Art
The process of iontophoresis was first described by LeDuc in 1908 and has since found wide commercial use in the delivery of ionically charged therapeutic agent molecules such as pilocarpine, lidocaine and dexamethasone across the skin of patients using an electromotive force. In this delivery method, ions bearing a positive charge are driven across the skin at the site of an electrolytic electrical system anode while ions bearing a negative charge are driven across the skin at the site of an electrolytic system cathode.
Generally, early iontophoretic devices included two electrodes attached by adhesive materials to a patient, each connected by a wire to a remote power supply, generally a microprocessor-controlled electrical instrument. While some may still be in use, more recently, self-contained wearable iontophoretic systems have been developed. These systems also include two electrodes fixed to patients by means of adhesive materials; however, they do not require external wires and are much smaller in size.
Generally, iontophoresis systems can be either voltage or current regulated. Voltage regulated designs are generally less complex and less costly to manufacture. With a voltage regulated design, the time required to deliver a full dose may vary significantly from patient to patient, because differences in skin resistance will cause differences in delivery current. Because of this, all patients may be forced to wear a patch for a longer time to compensate for the possibility of high skin resistance. This can also be a safety concern, as patients having relatively low skin resistance may experience higher than desirable currents that can cause skin irritation and/or allow the delivery of higher than desirable dosage rates to the systemic circulation of a patient. Current regulated systems, on the other hand, while more complex and costly to manufacture, enable a more consistent delivery rate that is less affected by variability in skin resistance. Thus, current regulated systems are generally more desirable.
It follows that subject skin safety provides a significant limitation to the use of iontophoresis. High levels of current and prolonged administration are considered to be undesirable, and include the possibility of skin burns. Additionally, introduction of drug or formulation excipients into the skin can produce irritation, sensitization, or cause other compound related adverse effects. In the case of topical corticosteroids, the Physicians' Desk Reference (PDR) lists drug-related adverse effects including (in decreasing order of occurrence): burning, itching, irritation, dryness, folliculitis, hypertrichosis, and others. Electrode dimensions for iontophoresis in a delivery pad preferably should be relatively large in area in order to enhance relatively even distribution of current and minimize the possibility of any locally high skin current density.
Delivery of dexamethasone by iontophoresis is now commonly used in physical therapy clinics for treatment of inflammation, and was first reported in 1963 by Murray et al (Journal of the APTA, Vol. 43 No 8 August 1963 pp 579-581). Typically, this is accomplished by loading dry electrode chambers with separately obtained aqueous solutions of dexamethasone sodium phosphate and saline, followed by an iontophoretic skin patch application to the patient in the clinic. In general, a course of treatment consists of up to six separate iontophoresis applications. The need for multiple applications represents an inconvenience to clinicians and patients, as patients must return to a clinic for each application.
Current systems available for dexamethasone iontophoresis involve loading a 4 mg/ml free-flowing liquid solution of dexamethasone into a patch at the time of use and an iontophoretic charge dosage of between 40 and 80 mA-minutes is typically applied thereafter. Estimates of the amount of dexamethasone delivered in this cycle have ranged from 10 micrograms (see Petelenz, Journal of Controlled Release, 20 (1992) pp 55-66) to 1.4 milligrams (Journal of Pharmaceutical Compounding Vol. 7 No 2 March/April 2003 pp 155-159). The need to obtain and load a separate solution of dexamethasone, of course, represents an inconvenience to clinicians and patients. Moreover, the necessity of adding the dexamethasone as a free-flowing liquid introduces a potential for over-filling, under-filling, or misdirection of dexamethasone solution into the reservoir. Liquids can also flow among the chambers of the patch while the patch is worn, which can alter the direction of current flow, cause adhesion failure, or even be lost from the patch with body movement.
A number of small clinical trials have also demonstrated that this dexamethasone iontophoresis process can be clinically effective. References regarding some of these are listed in Appendix A.
Others have reported a failure to demonstrate clinical efficacy with dexamethasone iontophoresis. See, for example, Runeson L, Haker E: Iontophoresis with cortisone in the treatment of lateral epicondylalgia (tennis elbow)—a double blind study (Scand J Med Sci Sports: 136-142, 2002).
Notably, a relatively recent attempt to confirm efficacy of dexamethasone iontophoresis in a large scale FDA phase III clinical trial failed to confirm effectiveness (Iomed, Inc., Salt Lake City, Press release May 1, 2001). Thus, despite 40 years of use, the evidence for clinical effectiveness of dexamethasone iontophoresis is considered anecdotal and, to date, the FDA has not authorized dexamethasone to be labeled for iontophoretic delivery or marketed in a co-packaged combination iontophoresis product.
Also of note is the fact that to date all known, previous attempts to measure efficacy of corticosteroid iontophoresis are based on clinician-applied devices. Clinicians are believed to be better trained to properly load the drug into the chamber and position the electrodes on the patient body, which can be very difficult for the patient to do in places not easily seen and/or accessible to the patient with both hands. If the electrodes of these previous devices are not properly placed on the body, there remains a possibility that the current may be concentrated only in reduced areas of good contact and this can lead to potential for skin damage. While advantages to having clinicians load and apply these devices exist, as indicated, the fact that patients must return to a clinic for each application represents a significant inconvenience.
With administration of corticosteroids, an important safety concern also relates to the amount of the compound released to the systemic blood circulation. Short term side effects associated with systemic corticosteroids include sleep disturbances, weight gain, and psychological effects. Longer term side effects include hypopituitary-adrenal-axis suppression, osteoporosis, muscle weakness, aggravation of diabetes mellitus, and others. Therefore, with delivery of corticosteroids by iontophoresis, it is of paramount safety concern to use conditions which minimize the release to systemic blood circulation.
To date, most clinical uses involving dexamethasone iontophoresis involve delivery devices with adjustable settings for current level and current duration time, but the clinician administering the iontophoresis does not have any knowledge as to whether the conditions selected facilitate release of corticosteroid to systemic blood circulation. In fact, a clinician desiring to improve clinical efficacy of iontophoresis will likely increase the current level and/or duration, unknowingly subjecting the patient to potentially increased dangers of systemic release of the corticosteroids.
Therefore, a need exists for a more clinically effective, skin-safe, systemically-safe and convenient iontophoretic delivery system for corticosteroids that enables delivery of a therapeutically effective amount in a relatively short time.